Taxol and Taxotere as well as their analogues of general formulae: ##STR1## which show notable anticancer and antileukaemia properties, are notable chemotherapeutic agents for the treatment of a certain number of cancers such as, for example, cancers of the breast, prostate, colon, stomach, kidney or testicles and more especially cancer of the ovaries.
In particular, in the general formula (I), Ar can represent an optionally substituted phenyl radical, R can represent a hydrogen atom or an acetyl radical or an N-substituted carbamoyl radical, R' represents a hydrogen atom or an N-substituted carbamoyl radical and R.sub.1 can represent a phenyl radical or a radical R.sub.2 --O-- in which R.sub.2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.
Taxol corresponds to the product of general formula (I) in which Ar and R.sub.1 represent a phenyl radical and R represents an acetyl radical and R' represents a hydrogen atom and Taxotere corresponds to the product of general formula (I) in which Ar represents a phenyl radical, R and R' represent a hydrogen atom and R.sub.1 represents a t-butoxy radical.
Taxol, which exists in the natural state in various species of yew in which it is found in small amounts, is difficult to isolate without completely destroying the plant. For example, taxol can be isolated according to the method of C. H. O. Huang et al., J. Natl. Prod., 49,665 (1986) which consists in treating the ground bark of Taxus brevifolia with methanol, in concentrating the extract, extracting the concentrate with dichloromethane, in again concentrating, in dispersing the residue in a hexane/acetone (1/1 by volume) mixture, and in purifying the soluble part by chromatography on a Florisil column to obtain crude taxol which is purified by successive recrystallizations from methanol/water and hexane/acetone mixtures, then by chromatography and again crystallization. The amounts of taxol thus extracted can represent from 0.005 to 0.017% of the part of the plant used.
Taxotere, which does not exist in the natural state, can be prepared by semi-synthesis from 10-deacetylbaccatin III of formula: ##STR2## according to the processes which are described, for example, in American U.S. Pat. Nos. 4,814,470 or 4,924,012 or in International Application PCT WO 92/09589.
Taxol can also be prepared by the processes which involve the use of 10-deacetylbaccatin III, either by passing through the intermediacy of Taxotere under the conditions described in American U.S. Pat. No. 4,857,653 or by esterification of baccatin III under the conditions described in European Patents EP 400,971 or EP 428,376 or by esterification of 10-deacetylbaccatin III and acetylation under the conditions described in American U.S. Pat. No. 4,924,011.
The various varieties of yew (Taxus baccata, Taxus brevifolia, Taxus canadensis, Taxus cupidata, Taxus floridana, Taxus media and Taxus wallichiana) contain taxane derivatives, the main ones of which are essentially taxol and 10-deacetylbaccatin III, the other derivatives being more particularly cephalomannin, 10-deacetyl-cephalomannin or baccatin III, optionally linked to sugars.
Whilst taxol is mainly found in the trunk and bark, 10-deacetylbaccatin III is essentially present in the leaves. Moreover, the 10-deacetylbaccatin III content in the leaves is generally much greater than that of taxol, whether the latter is present in the bark, trunk or in the leaves.
It results therefore that it is particularly important to be able to have available 10-deacetylbaccatin III which is essential to the preparation of much more significant amounts of taxol than by direct extraction from yews as well as to the preparation of Taxotere.
The extraction of 10-deacetylbaccatin III from yew leaves does not lead to complete destruction of the plant, whose leaves can be used again after each growth cycle.
Generally, the known methods for extracting taxane derivatives contained in various parts of the yew (bark, trunk, roots, leaves and the like) require the use of lengthy and expensive chromatographic techniques which do not make possible complete and quantitative separation of the taxane derivatives initially present in the plant.
According to the process described in American U.S. Pat. No. 4,814,470, which uses maceration of the needles in ethanol, extraction with an organic solvent, such as methylene chloride, and successively chromatographing, it is possible to isolate approximately 40% of the 10-deacetylbaccatin III contained in the leaves.
The various taxane-derived constituents present in the various parts of the yew can also be separated by methods using "reverse" liquid phase chromatography which are described, in particular, in International Application PCT WO 92/07842. These processes consist essentially in treating the crude yew extracts by "reverse" liquid phase chromatography through an adsorbent on which the taxane derivatives are fixed, eluting the taxane derivatives and in isolating them. According to this process, it is possible to isolate approximately 25% of the 10-deacetylbaccatin III contained in the leaves.